Seven IGFBPs has been described to modulate the IGF activity. IGFBPs transport IGFs, in which they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBPs structurally are characterized by three domains: the amino-terminal, the carboxi-terminal, and an intermedia or variable L-domain. Members of the IGFBP family exhibit 67–70% structural homology. The greatest homology among the IGFBPs is in the N- and C-terminal regions. Some IGFBPs bind to the extracellular matrix (IGFBP-2, -3, -5, and -6). In fact, a heparin-binding domain (HBD) has been identified in the C-terminal region of these binding proteins. IGFBP-5 is the most conserved IGFBP in mammals. Additionally, human and mouse IGFBP-5 are 97% identical. The IGFBPs bind IGFs with high affinity (kD ～0.1 nM), and this binding restricts the interaction of IGFs to their receptors. The release of the IGFs from IGFBP-5 is mediated by proteolysis; it has been described that IGFBP-5 is cleaved by ADAM-12, ADAM-9, C1s, and PAPPs (pregnancy-associated plasma proteases) A and A2. IGFBP-5 plays a key role in tissue repair and regeneration. IGFBP-5 is overexpressed in fibrotic lung tissues from patients with idiopathic pulmonary fibrosis. In vitro, IGFBP-5 induces the production of ECM components while in vivo, IGFBP-5 initiates the development of dermal and pulmonary fibrosis. In addition, IGFBP-5 induces lung fibroblast and mononuclear cell migration in an IGF-I–independent manner. Also, IGFBP-5 plays an important role in mammary development, involution, and breast cancer metastasis. IGFBP-5 has nuclear localization sequence that mediates β-importin-dependent translocation to the nucleus, where it interacts with the vitamin D receptor and modulates the vitamin D response in osteoblasts.